In human populations, depression shows strong co-morbidity with alcoholism. Greater understanding of the neurochemical mechanisms of depression, leading to better treatment, would therefore be expected to reduce the prevalence of alcoholism. The Porsolt swim test is widely used as an animal screening test for response to antidepressant compounds. In this test, mice are placed in a beaker of water, where they spend some amount of time swimming trying to escape, and the remainder of the time floating immobile. Compounds which decrease immobility time in this test, such as imipramine, are clinically effective antidepressant compounds in humans. We have searched for and identified mouse strains which show dramatic differences in immobility time in this Porsolt swim test. We are examining different neurochemical parameters in the different mouse strains, focusing in particular on aspects of serotonin neurotransmission, since most antidepressants act by influencing brain serotonin systems. We have also begun breeding F1 hybrids between high-immobility and low-immobility strains for analysis of the genetic transmission of the trait.